Chapter <1207> providesan overview of “leak test” methodologies (also termed technologies, approaches,or methods) as well as “package seal quality tests” useful for verification ofsterile product package integrity. More detailed recommendations for theselection, qualification, and use of leak test methods are presented in threesubchapters that address these specific topics:

第1207章概述了“泄漏测试”方法（也称为技术，方法或方法）以及“包装密封质量测试”，可用于验证无菌产品包装的完整性。关于泄漏测试方法的选择，鉴定和使用的更详细的建议，在以下三个子章节中进行了介绍，分别针对这些特定主题：

Package Integrity and Test MethodSelection <1207.1>包装完整性和测试方法选择

PackageIntegrity Leak Test Technologies <1207.2>包装完整性泄漏测试技术

PackageSeal Quality Test Methods <1207.3>包装密封质量测试方法

At the end of chapter SterileProduct Packaging—Integrity Evaluation <1207>, the Appendix:Definitions section defines terms as they are used in the context ofthis set of four general information chapters.

在《无菌产品包装-完整性评估1207》一章的末尾，“附录：定义”部分定义了在这套四个常规信息章节的上下文中使用的术语。

This chapter Package Integrity and Test Method Selection <1207.1> discussessterile package integrity assurance, provides information about package leaks,and describes a range of package integrity test methods. Package integrity verificationoccurs during three product life cycle phases: 1) the development andvalidation of the product–package system, 2) product manufacturing, and 3)commercial product shelf-life stability assessments.

本章包装完整性和测试方法选择<1207.1>讨论无菌包装完整性保证，提供有关包装泄漏的信息，并介绍一系列包装完整性测试方法。包装完整性验证在三个产品生命周期阶段进行：1）产品-包装系统的开发和验证，2）产品制造，以及3）商业产品货架寿命稳定性评估。

PACKAGE INTEGRITY AND TESTING DURING PRODUCTLIFE CYCLE

产品生命周期中的包装完整性和测试

Appropriate packaging for a sterile product can be determined on thebasis of a knowledge-gaining effort conducted during the product's life cycle.Package design fitness-for-use is incorporated into a packaging system byselecting the most appropriate components and packaging assembly. Adherence tothe design specifications is confirmed by performing ongoing process control.Some important points to consider in terms of design are discussed in thesection Package Integrity as a Function of Closure/Seal Type and Mechanics.Periodic assessment of the integrity provided by the components and the assemblycan confirm the consistency and quality of the product–package.

无菌产品的适当包装可以根据产品生命周期中获得的知识来确定。通过选择最合适的组件和包装组件，将适合使用的包装设计纳入包装系统。通过执行持续的过程控制，可以确保符合设计规范。在包装方面，作为密封/密封类型和力学的函数，讨论了一些在设计上要考虑的重要问题。定期评估组件和组件提供的完整性可以确认产品包装的一致性和质量。

PACKAGE DEVELOPMENT AND VALIDATION¹

包装开发和验证

Package Development

包装开发

Package development begins with the preparation of a product–packageprofile (e.g., user specification requirements), which considers the productend use, stability requirements, and method of manufacture, as well as theanticipated storage, shipment, and distribution environment. By using thisprospectively developed profile, one can select each package component'smaterials of construction, choose suitable component sources, and establish criticalphysical attributes and component dimensional tolerances. Each componentmaterial, with its critical dimensional tolerances, directly affects theintended integrity of the final packaged product. Assurance of packageintegrity originates from the use of appropriate materials, accurate andoptimum closing properties, matching dimensional fit, and consistent control ofprocesses used to assemble the closed package.

包装开发从准备产品包装简介（例如，用户规范要求）开始，其中考虑了产品最终用途、稳定性要求和制造方法，以及预期的存储、运输和分配环境。通过使用这种预期发展的轮廓，可以选择每个包装组件的构造材料，选择合适的组件来源，并建立关键的物理属性和组件尺寸公差。每种组件材料及其关键的尺寸公差都会直接影响最终包装产品的预期完整性。包装完整性的保证源于使用适当的材料，准确和最佳的密封性能，匹配的尺寸配合以及对用于组装密封包装的过程的一致控制。

The manner in which the package is formed or assembled into a finalproduct must be considered in the assurance of package integrity. Thus, thepackage undergoes a preliminary assessment at the end of the development phaseunder conditions representative of the marketed product manufacturing system.These conditions include processes such as component cleaning and sterilization,which are performed according to the established and approved user requirementspecifications. The appropriate seal conditions for each container type shouldbe defined in the development phase, unless the producer is using a common container–closuresystem and has significant experience and process knowledge regarding thissystem. Finally, the robustness of the manufactured product–package system maybe evaluated during the development phase by exposing a representative numberof product samples to specified storage, shipment, distribution, and finalproduct-use environments.

在保证包装完整性时，必须考虑包装形成或组装成最终产品的方式。因此，在代表市场产品制造系统的条件下，在开发阶段结束时对包装进行初步评估。这些条件包括根据已建立和批准的用户要求规格执行的组件清洁和消毒等过程。除非生产者使用通用的容器密闭系统，并且具有有关该系统的丰富经验和工艺知识，否则应在开发阶段定义每种容器类型的适当密封条件。最后，可以在开发阶段通过将代表性数量的产品样本暴露于指定的存储，运输，分配和最终产品使用环境中来评估制成品-包装系统的耐用性。

Development efforts should include studies that evaluate packageintegrity at the extremes of the finished product–package profile, not simplyat optimal conditions. Component lots may vary in specifiable attributes thatcould affect fitness for use. The physical characteristics of seal/containermaterials should be defined to ensure that the most extreme conditionsanticipated for cleaning and sterilization do not physically damage materialsin a manner that would adversely affect package integrity. Given the complexityof some sterile packages, it may be necessary that package integritydevelopment studies require multi-point analyses of test packages manufacturedwithin specified process parameters. The package tests selected for use inpackage development should be able to detect significant shifts in packageintegrity that result from specified process conditions.

开发工作应包括评估成品完整性的包装完整性的研究，而不仅仅是在最佳条件下进行。组件批次的特定属性可能有所不同，这可能会影响使用的适用性。应定义密封/容器材料的物理特性，以确保预期用于清洁和消毒的最极端条件不会以对包装完整性造成不利影响的方式物理损坏材料。考虑到某些无菌包装的复杂性，包装完整性开发研究可能需要对指定工艺参数内制造的测试包装进行多点分析。选择用于包装开发的包装测试应能够检测到由指定工艺条件引起的包装完整性的重大变化。

The quantities of packages to be tested must be sufficient to provideadequate assurance of package integrity and will likely vary on the basis of:1) the complexity of the product–package, 2) the specifics of the userspecification requirements, and 3) the prior experience of the producer. Appropriatespecifications and control ranges can be determined by using the informationgathered during package development. Next, these specifications and controlranges can be used to propose the initial user requirement specifications forthe production process.

要测试的包装数量必须足以确保包装完整性，并且可能会基于以下因素而变化：1）产品包装的复杂性； 2）用户规范要求的细节； 3）包装的完整性。生产者的先前经验。可以通过使用包装开发过程中收集的信息来确定适当的规格和控制范围。接下来，这些规格和控制范围可用于提出生产过程的初始用户需求规格。

The outputs of the packaging development phase include the final userrequirement specifications, which form the basis of purchasing specificationsfor package components. Also during the development phase, the final equipmentuser requirement specifications are developed for package material cleaning,sterilization, and forming; sealing or assembly equipment; and allied materialssupply and component feed systems. These user requirement specificationsprovide purchase specifications for the acquisition of equipment or for thevetting of potential contract manufacturers.

包装开发阶段的输出包括最终用户需求规格说明，这是购买包装组件规格的基础。同样在开发阶段，针对包装材料的清洁，消毒和成型，开发了最终的设备用户要求规格。密封或装配设备；以及相关的材料供应和组件进料系统。这些用户要求规格提供了用于购买设备或审核潜在合同制造商的购买规格。

Package Processing and Assembly Validation

包装加工和组装确认

Package integrity evaluation is generally part of a larger processvalidation activity for the overall production process. The scope depends uponthe product type and whether the organization has previous experience with thecontainer–closure system. Additional evaluations may be required for complexpackage systems, such as pre-filled syringes or packages made from unique form,fill, and seal processes.

包装完整性评估通常是整个生产过程中较大过程确认活动的一部分。范围取决于产品类型以及组织是否具有容器封闭系统的先前经验。对于复杂的包装系统，例如预灌装的注射器或由独特的成型，填充和密封过程制成的包装，可能需要进行其他评估。

All processes germane to the sterilization and formation of an integralsterile package are to be evaluated against the user requirement specificationsestablished in the package development phase. For example, package integrityshould be confirmed as a function of package component sterilization exposure,including possible re-sterilization. Package integrity verification should takeinto account the extremes of package assembly variables such as line speed,heat-sealing temperature, screw-cap application torque, and vial-cappingforces. Consideration should also be given to labeling and to secondary andtertiary packaging processes that could affect package integrity. Validationtest requirements should fit the statistical requirements and capabilities ofeach process, taking into account both package and package-line complexity, aswell as prior experience with similar product–packages.

与灭菌和整体无菌包装形成密切相关的所有过程均应根据包装开发阶段建立的用户要求规格进行评估。例如，包装完整性应根据包装组件的灭菌暴露（包括可能的重新灭菌）来确定。包装完整性验证应考虑包装组装变量的极端情况，例如线速度，热封温度，螺帽施加扭矩和小瓶盖紧力。还应考虑标签以及可能影响包装完整性的二级和三级包装过程。验证测试要求应适合每个过程的统计要求和功能，同时考虑到包装和包装线的复杂性，以及类似产品包装的先前经验。

Testing should be done duringtechnical transfer from the product development site to the manufacturing sitesto determine whether the user requirement specification targets and the controlranges established in development require any modification when packages aremade on a full manufacturing scale.

在从产品开发站点到制造站点的技术转移过程中，应进行测试，以确定在完整制造规模下进行包装时，是否需要修改开发过程中建立的用户要求规格指标和控制范围。

Successful validation will result in a package that meets its userrequirement specifications. The primary objective in package development andsubsequent validation is to arrive at a quality product–package prepared usingprocesses that reliably and consistently run within specified operatingparameters as defined in the user requirement specifications, yielding criticalpackage defects at a satisfactorily low rate. When performed, in-process andend-product package integrity testing should complement, not replace, thoroughpackage development efforts.

成功的确认将产生符合其用户要求规格的软件包。包装开发和后续验证的主要目标是，使用在用户要求规格中定义的指定操作参数范围内可靠且始终如一地运行的工艺来制备高质量的产品包装，以令人满意的低比率产生关键的包装缺陷。在执行过程中，过程中和最终产品包装的完整性测试应补充而不是代替彻底的包装开发工作。

PRODUCT MANUFACTURING

产品制造

To ensure the quality of the manufactured product–package, it iscritical to specify components of sufficient quality and to select vendorscarefully. The factors to consider include:

为了确保制成品包装的质量，至关重要的是要指定质量足够的组件并仔细选择供应商。要考虑的因素包括：

lResults of the initial vendor or supplier evaluation

初始供应商或供应商评估的结果

lDetermination of appropriate acceptance quality limits and statisticalsampling plan, or certification of selected vendor(s)

确定适当的验收质量限制和统计抽样计划，或对选定供应商进行认证

lVerification of incoming components, including statistical assessment ofquality against purchase specifications

验证来料组件，包括根据购买规格对质量进行统计评估

lProcedure(s) to determine how corrective and preventive actions are tobe put in place when a vendor falls short of quality expectations

确定当供应商未达到质量期望时应如何采取纠正和预防措施的程序

Package integrity should be re-evaluated when changes are required inpackage design, package materials, or manufacturing/processing conditions. Theextent of change control efforts should be evaluated on a case-by-case basis,and the level of testing required to support the change should be determinedand documented.

当包装设计、包装材料或制造/加工条件需要更改时，应重新评估包装完整性。应根据具体情况评估变更控制工作的范围，并应确定和记录支持变更所需的测试级别。

The proper combination of package leak tests, complementary package sealquality tests, and visual inspection checks for use in manufacturing willdepend on package failure results observed in earlier production validation andpackage development studies. The goal of such tests is to prevent, or identifyand remove, those defects of greatest concern, precluding shipment ofnonintegral container–closures that risk product contamination or physicochemicalstability loss. Correct processing procedures should be used to preventpackaged-product damage that is not readily detected after package assembly byinspection or by package testing technologies. Testing of production lotsamples can provide a measure of package integrity confirmation, if required.

包装泄漏测试，补充的包装密封质量测试以及用于制造的外观检查的适当组合，将取决于早期生产验证和包装开发研究中观察到的包装失效结果。此类测试的目的是防止或识别和消除那些最令人担忧的缺陷，其中包括装运可能损坏产品污染或理化稳定性的非整体容器-封闭容器。应使用正确的加工程序来防止包装产品损坏，这种损坏在包装后很难通过检查或包装测试技术检测到。如果需要，生产批次样品的测试可以提供包装完整性确认的措施。

Nondestructive leak tests of the entire manufactured lot may bepreferred for greater integrity assurance if the products are in commercial orclinical distribution and to provide an ongoing measure of product sealquality. The manufacturer should be able to justify the amount of testingrequired on the basis of statistical process control results generated duringthe validation phase, and later, on the basis of routine manufacturingproduct-quality trending analyses.

如果产品以商业或临床形式销售，并且为了提供对产品密封质量的持续衡量，则最好对整个制造批次进行无损泄漏测试，以确保更大的完整性。制造商应能够根据在验证阶段产生的统计过程控制结果，并随后基于常规制造产品质量趋势分析，证明所需的测试量是合理的。

Glass or plastic ampulsclosed by heat fusion are customarily subjected to 100% nondestructive leaktesting. Products sealed under vacuum require appropriate package assemblyvalidation supplemented by testing over time to ensure that the vacuum isretained. Similarly, packages that require a specific, non-reactive, inert gasheadspace require appropriate package assembly validation along with testingfor rise in oxygen content over time. For further information on this topic,see the Commercial Product Stability section that follows.

通常对通过热熔合封闭的玻璃或塑料安瓿瓶进行100％无损泄漏测试。在真空下密封的产品需要适当的包装组装验证，并通过长期测试加以补充，以确保保持真空。类似地，需要特定的，非反应性的惰性气体顶部空间的包装，也需要进行适当的包装组装确认，并测试氧含量随时间的升高。有关此主题的更多信息，请参见下面的“商品稳定性”部分。

COMMERCIAL PRODUCT STABILITY

商业产品稳定性

Container–closure integrity tests have been recommended as alternativesto sterility testing as part of commercial product stability programs. The goalis to ensure package integrity as a function of long-term product storage (1). [NOTE—Package integrity tests do not replace product releasesterility tests.] Physicochemical test methods or even microbiological testsare generally more sensitive than sterility testing for detecting loss ofproduct–packaging integrity and sterility assurance. Industry experiencesuggests that the potential for false-positive or false-negative results may bereduced by using packaging integrity testing, compared with sterility tests.Testing product for sterility is a poor measure of product–package integrityand also will not ensure product–package integrity over the shelf life of theproduct when performed as part of the stability program. In addition, a packagemay be in no danger of microbial ingress and yet be unable to maintain anonreactive gas headspace or provide an effective vapor barrier. Microbiologicalingress tests are not sufficient to ensure leak tightness with respect to gasexchange or evaporation and are limited in their ability to detect all leaksthat have the potential to allow microbial ingress.

建议将容器密闭完整性测试作为无菌测试的替代方法，作为商业产品稳定性计划的一部分。目的是确保包装的完整性作为长期产品存储的功能（1）。 [注意—包装完整性测试不能代替产品放行的无菌测试。对于检测产品包装完整性和无菌性的损失，理化测试方法甚至微生物测试通常比无菌性测试更敏感。行业经验表明，与无菌测试相比，使用包装完整性测试可减少产生假阳性或假阴性结果的可能性。测试产品的无菌性不能很好地衡量产品-包装的完整性，并且在作为稳定性计划的一部分执行时，也不能确保产品-包装在产品的保质期内的完整性。另外，包装可能没有微生物入侵的危险，但仍不能维持非反应性气体的顶部空间或提供有效的蒸汽屏障。微生物侵入测试不足以确保与气体交换或蒸发相关的密封性，并且其检测所有可能允许微生物侵入的泄漏的能力受到限制。

Package integrity tests selected to support marketed-product stabilitystudies should be able to verify the absence of leak pathways that could leadto product leakage, gas exchange (where a consideration), or loss of sterilityassurance. It is possible for the product itself to interfere with the abilityof leak test methodologies to detect package defects. For example,proteinaceous ingredients or even salts may clog leak pathways, inhibiting leakdetection by vacuum decay or mass extraction. Before selecting a leak testmethod for evaluating package integrity over the product shelflife, it isprudent to explore the product's potential to interfere with the selected leaktest method's capability, both initially after package assembly and over time.

为支持上市产品稳定性研究而选择的包装完整性测试，应能够验证不存在可能导致产品泄漏、气体交换（考虑在内）或丧失无菌保证的泄漏途径。产品本身可能会干扰泄漏测试方法检测包装缺陷的能力。例如，蛋白质成分甚至盐类可能会堵塞泄漏路径，从而通过真空衰减或质量提取抑制泄漏检测。在选择一种泄漏测试方法以评估产品在整个保质期内的包装完整性之前，应谨慎考虑产品在包装后最初以及在一段时间后是否会干扰所选泄漏测试方法的功能。

In some situations, it is appropriate to substitute a package test thatdoes not directly measure leakage but that provides other relevant informationabout package integrity. For example, headspace content analysis that verifiesthe continued presence of headspace gases or subatmospheric pressure over timedoes not explicitly measure leakage flow or defect presence but satisfactoryresults support the absence of leakage that could jeopardize sterility. Therequired duration for monitoring container vacuum or headspace gas contentmaintenance that equates to microbial barrier assurance can be predicted on thebasis of gas flow kinetics, should a leak pathway exist that is large enough toallow microbial entry.

在某些情况下，可以替代不直接测量泄漏，但可以提供有关包装完整性的其他相关信息的包装测试。例如，验证顶空气体或低于大气压的持续存在的顶空含量分析不能明确测量泄漏流量或缺陷的存在，但令人满意的结果支持不存在会危害无菌性的泄漏。如果存在足够大的允许微生物进入的泄漏通道，则可以根据气体流动动力学预测监视容器真空或顶空气体含量维持所需的相当于微生物屏障保证的持续时间。

Stability-test samples intended for package integrity evaluation arekept at labelled storage conditions for the marketed product. [NOTE—Thenegative effect of potential storage extremes on product–package integrityshould be explored during package development and the findings used to definelabelled storage condition restrictions.] The test-sample quantities to beintegrity tested at each stability-testing time point should be relevant andsufficiently representative of the purpose of stability testing, which is toindicate whether integrity is affected by the stability conditions. The latterselection of sample quantity should take into account all prior development andvalidation testing. If an integrity test causes no damage to the product orpackage, samples that pass package integrity testing may be further used in thestability testing for that specific test period or interval. However, samplesshould not be tested for package integrity at one time point (e.g., 12 months)and then stored for further stability testing at a later time point (e.g., 24months). Furthermore, all test samples earmarked for integrity verificationover the course of the stability study may be checked for integrity beforeplacement on stability if a nondestructive leak test method is used. In thisway, subsequent integrity failures will be attributed to stability storage,rather than other causes.

打算用于包装完整性评估的稳定性测试样品应保存在市售产品的标示存储条件下。[注意—在包装开发过程中，应探索潜在的极端存储对产品-包装完整性的负面影响，并使用发现的结果来定义标记的存储条件限制。]应在每个稳定性测试时间点进行完整性测试的测试样品数量与稳定性测试的目的相关并且足以代表稳定性测试的目的，即表明完整性是否受稳定性条件的影响。后一种样品数量的选择应考虑所有先前的开发和验证测试。如果完整性测试未对产品或包装造成损坏，则通过包装完整性测试的样品可以在该特定测试时间段或间隔内进一步用于稳定性测试。但是，不应在一个时间点（例如12个月）测试样品的包装完整性，然后再在以后的时间点（例如24个月）保存样品以进行进一步的稳定性测试。此外，如果使用非破坏性泄漏测试方法，则在稳定性研究之前，所有指定用于完整性验证的测试样品都可以进行完整性检查。这样，后续的完整性故障将归因于稳定性存储，而不是其他原因。

Package Integrity as a Function of Closure/SealType and Mechanics

包装完整性与密封/密封类型和力学的关系

This section discusses various closure/seal systems and how each typefunctions mechanically to ensure package integrity.

本节讨论各种封闭/密封系统以及每种类型的机械作用以确保包装的完整性。

PHYSICALLY MATED CLOSURE SYSTEMS

物理配对的关闭系统

Closure application achieves the close physical mating of two surfacesthat often are dissimilar. Such closure systems include the interference fit ofa plunger inserted in a syringe barrel, the compression fit of an elastomericclosure capped onto a vial finish surface, and the application force of ascrew-cap torqued onto a bottle. Such physically mated surfaces are not bondedtogether; therefore, a tiny gap exists, even between well-closed components.Nevertheless, when properly designed and assembled, closure systems fittogether such that liquid leakage (and microbial ingress) are prevented and gasmigration is limited. Regarding screw-thread closures such as those used forophthalmic-product dropper bottles, the threaded pathway does not provide abarrier to microbial ingress or liquid product leakage. The actual barrier toleakage is afforded by inner cap surfaces pressing against the package opening,in some cases aided by a secondary gasket or plug.

封闭应用可实现两个通常不相似的表面的紧密物理配合。这种封闭系统包括插入注射器针筒中的柱塞的过盈配合，盖在小瓶精加工表面上的弹性封闭体的压配合以及拧到瓶上的螺帽的施加力。此类物理匹配的表面未粘合在一起；因此，即使在封闭的组件之间也存在微小的间隙。然而，当正确设计和组装时，封闭系统可以装配在一起，从而防止液体泄漏（和微生物进入），并限制了气体迁移。关于诸如用于眼科产品滴管瓶的那些螺纹封闭件，螺纹通道不为微生物进入或液体产品泄漏提供屏障。内盖表面压在包装开口上可以提供真正的防渗漏功能，在某些情况下，还可以使用辅助垫圈或塞子。

PHYSICOCHEMICALLY BONDED CLOSURE SYSTEMS

物理化学键合关闭系统

Seals are formed when two similar or dissimilar surfaces arephysicochemically bonded together. One example is the formation and sealing ofcontiguous containers from a single material (e.g., glass or plastic ampuls).In “form, fill, and seal” systems, sheets of material are put together by meansof a heat or ultrasonic welding process. Two dissimilar materials may be joinedusing an intermediate bonding material. Fully fused seals inherently blockliquid leakage and microbial ingress;, however, gaseous leakage and permeationmay be evident. In some cases, form, fill, and seal products may have internalfrangible seals that are designed to open under defined use conditions. Inaddition, some form, fill, and seal products require a cover that can serve asa sterility-protecting barrier over constructed ports; the ports will be usedto withdraw product during use.

当两个相似或不相似的表面物理化学结合在一起时，就会形成密封。一个例子是用单一材料（例如玻璃或塑料安瓿）形成和密封连续的容器。在“成型、填充和密封”系统中，材料片是通过加热或超声焊接工艺组装在一起的。可以使用中间结合材料将两种不同的材料结合起来。完全熔融密封会固有地阻止液体泄漏和微生物进入；但是，气体泄漏和渗透可能很明显。在某些情况下，成型，填充和密封产品可能具有内部易碎的密封件，这些密封件设计为在定义的使用条件下打开。另外，某些形式，填充和密封产品需要盖，可以用作已建端口上的无菌保护屏障。这些端口将在使用过程中用于撤回产品。

VENT FILTRATION CLOSURE SYSTEMS

透气过滤封闭系统

Vent filtration closure systems include structures designed to filterout or otherwise limit microbial ingress while still allowing air exchange orproduct passage. For example, kit packages of drug/device combination productsare often closed using a hydrophobic porous-barrier lidding material. Theporous barrier is intended to allow gas movement in and out of the packagewhile preventing the ingress of airborne viable or nonviable particulate matterby means of a tortuous path matrix provided by filter-like barrier material. Liddingmaterial of coated paper or flashspun polyolefin fibers sealed onto a plastictray is an example of this type of package–closure system.

透气过滤封闭系统包括旨在过滤或限制微生物进入的结构，同时仍允许空气交换或产品通过。例如，经常使用疏水性多孔阻隔盖材料封闭药物/装置组合产品的试剂盒包装。多孔阻隔层旨在允许气体进出包装，同时借助由过滤器状阻隔层材料提供的曲折路径矩阵防止空气中的可生存或不可生存的颗粒物质进入。密封在塑料托盘上的铜版纸或闪纺聚烯烃纤维的覆盖材料就是这种包装盒/封闭系统的一个例子。

MULTIPLE-DOSE PRODUCT MICROBIAL-BLOCKAGE CLOSURESYSTEMS

多剂量产品微生物阻隔系统

Multiple-dose product closure systems are designed to allow productegress while preventing microbial ingress. Some multiple-dose ophthalmic dosageform package closures are designed with filters, porous plugs, or othermechanical systems that allow product to be dispensed while blocking microbialingress. Other sophisticated multi-dose packages are designed with closuresthat automatically close between intermittent dosing to prevent microbialentry. Product development and validation studies for these multi-dose productsshould be designed to demonstrate sterility assurance under use conditions andalso throughout the product shelflife. [NOTE—This section does not apply toelastomeric closures on multi-dose parenteral packages that are intended toreseal when punctured.]

多剂量产品封闭系统旨在允许产品流出，同时防止微生物入侵。一些多剂量眼用剂型包装的闭合件设计有过滤器，多孔塞或其他机械系统，可在分配产品时阻止微生物的进入。其他复杂的多剂量包装均设计有封闭装置，可在间歇给药之间自动封闭，以防止微生物进入。这些多剂量产品的产品开发和验证研究应旨在证明在使用条件下以及整个产品保质期内的无菌性。 [注意—本节不适用于打算在刺穿时重新密封的多剂量肠胃外包装上的弹性封闭物。

TEST METHOD SELECTION CRITERIA

测试方法选择标准

No single package leak test or package seal quality test method isapplicable to all product–package systems. Some product–packages may requiremore than one test method during the product life cycle. Package test methodselection as a function of product life-cycle phase, along with importantintegrity considerations, are discussed in the section Package Integrity and TestingDuring Product Life Cycle (see above). A broad discussion of additionalselection criteria for leak test methods follows. Specific leak test methodexamples are provided for informational purposes but are not intended asrecommendations. The attributes and general capabilities of tests can be foundin chapter 1207.2 and are helpful inthe method selection process.

没有一种单独的包装泄漏测试或包装密封质量测试方法适用于所有产品-包装系统。在产品生命周期中，某些产品包装可能需要不止一种测试方法。根据产品生命周期阶段选择包装测试方法以及重要的完整性注意事项，将在“产品生命周期中的包装完整性和测试”部分中进行讨论（请参见上文）。接下来将对泄漏测试方法的其他选择标准进行广泛讨论。提供特定的泄漏测试方法示例仅供参考，但不作为建议。测试的属性和一般功能可以在<1207.2>中找到，这对方法选择过程很有帮助。

Package Contents

包装内容

When selecting a leak test method, the first determining factor is thenature of the package contents. Whether the package contains a liquid or solidformulation, and whether it contains a headspace of inert gas, air, vacuum, oreven no headspace at all, will influence the choice of leak test method. Forexample, if testing liquid-filled packages by vacuum decay or mass extraction,the test sample is placed in a test chamber, and sufficient vacuum is appliedto volatilize liquid product located in the leak path, triggering a measurablerise in test chamber pressure and/or mass flow. However, vacuum exposure maytrigger some formulations to solidify inside leak paths, thereby blockingleakage flow and making vacuum decay or mass extraction ineffective.Alternatively, electrical conductivity and capacitance tests can be used ifleak testing liquid-filled packages, but only if the product is more electricallyconductive than the package materials. The final choice of method may be influencedby the interaction between the leak test method and the product formulation.Clearly, the test method selected should be verified by the end-user for thespecific product–package application.

选择泄漏测试方法时，第一个决定因素是包装内容物的性质。包装是否包含液体或固体制剂，以及是否包含惰性气体，空气，真空的顶部空间，甚至根本没有顶部空间，都会影响泄漏测试方法的选择。例如，如果通过真空衰减或质量提取来测试充满液体的包装，则将测试样品放置在测试室中，并施加足够的真空以使位于泄漏路径中的液体产品挥发，从而触发测试室压力的可测量上升和/或质量流量。但是，真空暴露可能会触发某些配方在泄漏路径内部固化，从而阻止泄漏流并使真空衰减或质量提取无效。另外，如果对液体填充的包装进行泄漏测试，也可以使用电导率和电容测试，但前提是产品的导电性要比包装材料高。方法的最终选择可能会受到泄漏测试方法与产品配方之间相互作用的影响。显然，所选的测试方法应由最终用户针对特定产品-包装应用进行验证。

Package Design, Materials of Construction, andMechanics

包装设计，构造材料和力学

Packages vary widely in their design, their materials of construction,and the mechanisms whereby package closure is affected. Each of these variablesinfluences the choice of leak test method, as the following examplesillustrate.

包装在其设计，构造材料以及影响包装闭合的机制方面差异很大。这些变量中的每一个都会影响泄漏测试方法的选择，如以下示例所示。

RIGID VERSUS FLEXIBLE PACKAGES

刚性包装vs柔性包装

Rigid (nonporous) packages can tolerate the pressure or vacuum-challengeconditions required in several leak tests, including tracer-liquid ingress,vacuum decay, mass extraction, and some tracer-gas tests. In contrast, someflexible packages can tolerate differential-pressure test conditions only ifspecial tooling is used to restrict package expansion and prevent subsequentseal damage. Package restriction is key to ensuring that consistentdifferential-pressure conditions are maintained across the package barrier.

刚性（无孔）包装可以承受多种泄漏测试所需的压力或真空挑战条件，包括示踪剂液体进入，真空衰减，质量提取和某些示踪剂气体测试。相比之下，某些柔性包装仅在使用特殊工具限制包装膨胀并防止随后的密封损坏的情况下才可以承受差压测试条件。包装限制是确保整个包装屏障保持一致的压差条件的关键。

MOVEABLE VERSUS FIXED COMPONENTS

可动组件vs固定组件

Moveable package components, such as syringe stoppers (plungers or pistons),may require restraint to prevent their dislocation during thedifferential-pressure conditions that occur in a majority of leak test methods(e.g., tracer-liquid test, pressure or vacuum decay test, mass extraction test,bubble emission test, and microbial challenge by immersion test).

可移动的包装组件（例如注射器塞子（柱塞或活塞））可能需要约束以防止其在大多数泄漏测试方法中脱位（例如，示踪剂液体测试，压力或真空衰减测试，质量提取测试，气泡排放测试以及通过浸没测试进行的微生物攻击）。

POLYMERIC MATERIALS

高分子材料

Package materials such as plastics and some elastomers, when exposed tovacuum conditions, may outgas volatiles that raise vacuum-decay leak testresults as well as mass extraction results, falsely implicating packageleakage. In a similar manner, erroneous bubble emission test results may resultfrom the release of air sorbed onto submerged package surfaces; this can occurupon initial vacuum exertion. Plastic packages that are highly permeable totracer gases may not be compatible with helium tracer gas leak detection, ashelium permeating through the package could be mistaken for package leakage.Special fixturing to limit tracer gas permeation effects and isolate tracer gasexposure to the seal area under test has been used to mitigate such difficulties.

当包装材料（例如塑料和某些弹性体）暴露于真空条件下时，可能会释放出挥发物，从而提高真空衰减泄漏测试结果和质量提取结果，从而错误地暗示了包装泄漏状况。以类似的方式，错误的气泡排放测试结果可能是由于吸收到浸没在包装表面上的空气的释放而导致的；这可能在最初施加真空时发生。示踪气体具有高渗透性的塑料包装可能与氦气示踪气体泄漏检测不兼容，因为透过包装的氦气可能会误认为包装泄漏。为了减轻这种困难，已经使用特殊的夹具来限制示踪气体的渗透效果，并隔离示踪气体暴露于被测密封区域。

METALLIC MATERIALS

金属材料

Packages made of foil laminate materials may prove incompatible withelectrical conductivity and capacitance leak detection, which works best withrelatively nonconductive package materials. However, aluminum caps used tosecure vials closed with elastomeric closures pose no hindrance to electricalconductivity and capacitance tests, even for finding leaks located between theclosure and the vial finish.

由箔层压材料制成的包装可能证明与电导率和电容泄漏检测不兼容，这在相对不导电的包装材料中效果最佳。但是，用于固定用弹性密封件密封的小瓶的铝盖即使在发现密封件和小瓶瓶口之间的泄漏时也不会妨碍电导率和电容测试。

TRANSPARENT VERSUS OPAQUE MATERIALS

透明材料 vs不透明材料

Packages made of transparent or translucent materials allow for visualinspection and electromagnetic wave passage. Therefore, transparent ortranslucent materials can be tested by laser-based gas headspace analysistechniques, as well as tracer-liquid ingress or microbial ingress. Opaquepackages are incompatible with these testing approaches.

用透明或半透明材料制成的包装可进行目视检查和电磁波通过。因此，可以通过基于激光的气体顶空分析技术以及示踪剂液体进入或微生物进入来测试透明或半透明的材料。不透明的包装与这些测试方法不兼容。

POROUS VERSUS NONPOROUS MATERIALS

多孔异种材料

It is common for drug/device or drug/drug combination product–packagesto include a hydrophobic porous barrier material to facilitate sterilantpenetration. For example, a plastic tray may be sealed with a lidding materialof flashspun polyolefin fiber or coated paper. The nonporous components of sucha packaging system (e.g., the tray), or any bonds formed between the components(e.g., at the tray-lidding interface) may require testing by physicochemicalmeans such as vacuum decay, mass extraction, or tracer-liquid tests. Tests toevaluate the porous structures of such packaging are not described in thischapter; instead, the reader is advised to consult medical-device packagingreferences.

药品/器械或药品/药品组合产品包装通常包含疏水性多孔阻隔材料，以促进消毒剂的渗透。例如，塑料托盘可以用闪纺聚烯烃纤维或涂层纸的覆盖材料密封。此类包装系统的无孔组件（例如，托盘），或在组件之间形成的任何结合（例如，在托盘与盖子的界面处）都可能需要通过物理化学手段（例如真空衰减，质量提取或示踪液体）进行测试测试。本章未介绍评估此类包装的多孔结构的测试；替代地，建议读者查阅医疗器械包装参考。

MULTIDOSE-PRODUCT, MICROBIAL BLOCKAGE CLOSURESYSTEMS

多剂量产品，微生物阻隔封闭系统

Some unique product–package closure components are designed to allowliquid or semi-solid product egress, while still preventing microbial ingress(see VentFiltration Closure Systems section, above). For these container–closures,physicochemical leak tests are essential to check the integrity of thepackaging system, and additional microbiological challenge tests may benecessary to simulate product sterility risks posed by routine product use (2).

一些独特的产品包装封闭组件设计为允许液体或半固体产品流出，同时仍防止微生物入侵（请参见上方的“透气过滤封闭系统”部分）。对于这些容器密封，理化泄漏测试对于检查包装系统的完整性是必不可少的，并且可能还需要进行其他微生物挑战测试来模拟常规产品使用所带来的产品无菌风险（2）。

Product–Package Maximum Allowable Leakage

产品-包装最大允许泄漏

Most package types demonstrate at least miniscule gaseous leakage pluspermeation through the package materials of construction, even when optimallydesigned and assembled. Therefore, with the exception of glass ampuls, it isnot practical to require that all packages be absolutely free of leakage aswell as permeation; rather, it is the significance of leakage rate in relationto product quality that must be considered. In other words, the maximumallowable rate of leakage into and out of intact packages should be such thatthere is no effect on product safety and inconsequential effect on theproduct's physicochemical stability. Products fall into three categoriesregarding maximum allowable leakage: 1) products for which the maximumallowable leakage rate must preserve product sterility (gas headspace contentbeing irrelevant) and, therefore, the package must block all liquid passage; 2)products for which the package must preserve product sterility and also preservepackage headspace gas content or vacuum level; and 3) products for which themaximum allowable leakage rate is defined only in terms of microbial ingressprevention, as the package must still allow for liquid or gas passage.Selection of the leak test method should take into account the method's abilityto detect leaks at or near the maximum allowable leakage limit specific for theproduct–package. Further discussion and examples follow.

大多数包装类型，即使经过最佳设计和组装，也至少会显示出最小的气体泄漏以及通过结构包装材料的渗透。因此，除了玻璃瓶外，要求所有包装绝对没有泄漏和渗透是不切实际的。相反，必须考虑泄漏率相对于产品质量的重要性。换句话说，进出完整包装的最大允许泄漏率应确保对产品安全性没有影响，而且对产品的理化稳定性没有影响。关于最大允许泄漏，产品可分为三类：1）最大允许泄漏率必须保持产品无菌性的产品（气体顶空含量无关），因此，包装必须阻塞所有液体通过； 2）包装必须保持产品无菌性并且还必须保留包装顶空气体含量或真空度的产品； 3）产品的最大允许泄漏率仅在防止微生物进入方面进行定义，因为包装必须仍允许液体或气体通过。泄漏测试方法的选择应考虑该方法检测产品或包装特定的最大允许泄漏限值或附近的泄漏的能力。接下来是进一步的讨论和示例。

STERILITY MUST BE PRESERVED; GAS HEADSPACEPRESERVATION IS NOT CRITICAL

必须保持无菌状态；气体顶空保护不是至关重要的

The first product category consists of products for which the maximumallowable leakage ensures sterility preservation, while gas headspacepreservation (e.g., ambient pressure air) is of no concern. During packagedevelopment, it is recommended to use validated leak test methods capable ofdetecting the smallest leaks that have even a remote chance of posing anythreat to the sterility assurance of the product. Evidence shows that thenarrowest package leak orifice that runs any risk of liquid leakage orliquid-borne microbial ingress is approximately 0.1–0.2 µm in nominal diameter(3,4). Tracer gas tests sensitive enough to quantitatively analyze leakagethrough leak paths of this size and much smaller may be used. Such tests providevaluable information on the relationships among package design, component fit,package assembly parameters, and leakage rate, even in the absence of packagedefects.

第一类产品包括最大允许泄漏量确保无菌的产品，而气体顶空的保存（例如环境压力空气）则无关紧要。在包装开发过程中，建议使用经过验证的泄漏测试方法，该方法能够检测出最小的泄漏，甚至极有可能对产品的无菌保证造成任何威胁。有证据表明，最窄的包装泄漏孔的标称直径（3,4）大约有0.1–0.2 µm，存在任何液体泄漏或液体传播的微生物进入的危险。示踪气体测试足够灵敏，可以定量分析通过这种尺寸甚至更小泄漏路径的泄漏。这样的测试即使在没有包装缺陷的情况下，也可以提供有关包装设计、组件装配、包装装配参数和泄漏率之间关系的有价值的信息。

Leak testing of packages filled with product during the later phases ofthe product life cycle requires the use of other tests. Leak test methodsavailable for this phase of the product life cycle are generally capable ofreliably detecting defects of a few micrometers and larger. Examples of leaktests that might be considered include vacuum or pressure-decay tests, massextraction, electrical conductivity and capacitance tests, and liquid tests.

在产品生命周期的后期阶段，对装有产品的包装进行泄漏测试需要使用其他测试。在产品生命周期的此阶段可用的泄漏测试方法通常能够可靠地检测几微米甚至更大的缺陷。可以考虑的泄漏测试示例包括真空或压力衰减测试，质量提取，电导率和电容测试以及液体测试。

STERILITY MUST BE PRESERVED; GAS HEADSPACECONTENT IS CRITICAL

必须保持无菌状态；气体顶空含量至关重要

The second category includes those products that require criticalgaseous headspace or vacuum preservation to maintain productstability within physicochemical specification limits. The maximum allowableleakage for such packages is typically less than that for products that merelyrequire sterility assurance. Appropriate leak tests for this product categoryinclude methods that monitor package headspace pressure or gas content, ortracer gas test methods capable of the smallest leak detection. The limit ofdetection for such methods is a function of the method's ability to accuratelymeasure package headspace content or vacuum at the product acceptance limit,given the package headspace volume and the time lapse after package assembly.

第二类包括需要关键的气态顶空或真空保存以将产品稳定性保持在理化指标范围内的那些产品。这种包装的最大允许泄漏通常小于仅需要无菌保证的产品的最大允许泄漏。适用于此产品类别的泄漏测试包括监视包装顶部空间压力或气体含量的方法，或具有最小泄漏检测能力的示踪气体测试方法。在给定包装顶空体积和包装后经过的时间的情况下，此类方法的探测极限取决于该方法在产品接受极限下准确测量包装顶空含量或真空度的能力。

STERILITY MUST BE PRESERVED; GAS AND/OR PRODUCTPASSAGE IS REQUIRED

必须保持无菌状态；需要气体和/或产品通过

A third category exists in which the maximum allowable leakage for thepackage–closure system is defined in terms of microbial ingress prevention(i.e., sterility preservation), while at the same time, gas and/or product passagepast the closure system is required. For example, a tray or pouch that isclosed using a breathable porous film or lidding material is designed to blockentry of airborne microorganisms and particulates while allowing passage of airand/or sterilant gas. As a second example, some closures of multiple-dose ophthalmicformulation packages are designed to dispense sterile liquid or semi-solidproduct while preventing liquid-borne microbial entry by use of filters, porousplugs, or other mechanisms. The maximum allowable leakage for these closureseals may not be fully defined in terms of fluid flow rate or leak size measurementsbut may also require incorporation of unique microbial ingress preventionspecifications. The success of the closure system depends on its ability toprevent the entry of microorganisms. Test methods for evaluation of suchpackaging systems are not yet fully defined and, therefore, are not included inthis chapter.

存在第三类，其中，包装-封闭系统的最大允许泄漏是根据防止微生物侵入（即保持无菌性）来定义的，同时，气体和/或产品需要通过封闭系统。例如，使用透气的多孔膜或盖材料封闭的托盘或袋被设计成在允许空气和/或灭菌气体通过的同时，阻止空气中的微生物和微粒进入。作为第二个例子，多剂量眼用制剂包装的一些封闭物被设计成分配无菌液体或半固体产品，同时通过使用过滤器，多孔塞或其他机制防止液体传播的微生物进入。这些封闭密封件的最大允许泄漏可能无法根据流体流速或泄漏尺寸的测量来完全确定，但可能还需要结合独特的防止微生物进入的规范。封闭系统的成功取决于其防止微生物进入的能力。评估此类包装系统的测试方法尚未完全定义，因此，本章中不包括。

Deterministic versus Probabilistic Methods

确定性方法 vs概率性方法

A “deterministic leak test method” is one in which the leakage event isbased on phenomena that follow a predictable chain of events, and leakage ismeasured using physicochemical technologies that are readily controlled andmonitored, yielding objective quantitative data. Most deterministic leak testmethods rely on the predictable movement of gas that inevitably occurs throughan open leak path, given specific differential pressure or partial pressuretest conditions (e.g., tracer gas, laser-based gas headspace analysis, pressuredecay, vacuum decay, and mass extraction). A few deterministic leak testmethods (e.g., electrical conductivity and capacitance tests) rely on the morepredictable presence of liquid near a leak path, rather than the lesspredictable movement of liquid through a leak. Deterministic methods can bevalidated and shown capable of reproducibly detecting small leaks at clearlydefined limits of detection. Because the majority of deterministic leak testmethods described in this chapter require no special test sample preparation,sample preparation error is eliminated. For these reasons, these deterministicleak test methods can be readily validated for accuracy and precision and areable to meet clearly defined limits of detection.

“确定性泄漏测试方法”是一种泄漏事件，该泄漏事件基于遵循可预测事件链的现象，并使用易于控制和监控的物理化学技术对泄漏进行测量，从而得出客观的定量数据。给定特定的压差或分压测试条件（例如，示踪气体，基于激光的气体顶空分析，压力衰减，真空衰减和大量提取）。一些确定性的泄漏测试方法（例如，电导率和电容测试）依赖于泄漏路径附近的液体更可预测的存在，而不是液体通过泄漏的可预测性较低。确定性方法可以得到确认，并显示出能够在明确定义的探测极限下可重复检测小泄漏的方法。由于本章中介绍的大多数确定性泄漏测试方法均不需要特殊的样品制备方法，因此消除了样品制备误差。由于这些原因，这些确定性的泄漏测试方法可以很容易地验证准确性和精密度，并且能够满足明确定义的探测极限。

A “probabilistic leak test method” is stochastic in nature in that itrelies on a series of sequential and/or simultaneous events that are associatedwith uncertainties, each associated with random outcomes described byprobability distributions. Thus, the findings are associated with uncertaintiesthat necessitate large sample sizes and rigorous test condition controls toobtain meaningful results. Typically, sample size and test condition rigor areinversely related to leak size, and therefore reliable and predictable probabilisticleak test methods are more difficult to design, develop, validate, andimplement. Probabilistic leak tests, while useful leak detection tools, are notpreferred for definitive package integrity verification. Probabilistic methodsare most beneficial when the product–package system proves incompatible withdeterministic methods, or when method outcome requirements demand aprobabilistic testing approach. Probabilistic methods include microbialchallenge tests, bubble emission tests, tracer liquid tests (employing eitherqualitative or quantitative measurement methods), and tracer gas tests by thesniffer probe approach. Probabilistic method selection is often based on theneed for a specific test result outcome. For example, a microbiological challengetest may aid in understanding the risks to package sterility posed by specificpackage materials or package designs. To pinpoint package defect locations, itmay be suitable to use bubble emission, tracer liquid, or tracer gas snifferprobe tests.

“概率性泄漏测试方法”本质上是随机的，因为它依赖于一系列与不确定性相关的顺序和/或同时发生的事件，每个事件都与概率分布所描述的随机结果相关。因此，这些发现与不确定性相关，不确定性需要大样本量和严格的测试条件控制才能获得有意义的结果。通常，样本量和测试条件的严格性与泄漏量成反比，因此可靠，可预测的概率泄漏测试方法更难以设计，开发，验证和实施。概率泄漏测试虽然是有用的泄漏检测工具，但对于确定的包装完整性验证不是首选。当产品包装系统被证明与确定性方法不兼容时，或者当方法结果要求需要概率性测试方法时，概率性方法最有益。概率性方法包括微生物挑战测试，气泡排放测试，示踪剂液体测试（采用定性或定量测量方法）以及通过嗅探探针法进行的示踪气体测试。概率性方法的选择通常基于对特定测试结果的需求。例如，微生物挑战试验可能有助于理解特定包装材料或包装设计对包装无菌性造成的风险。为了查明包装缺陷的位置，可能适合使用气泡发射，示踪液体或示踪气体嗅探探针测试。

More information on the probabilistic nature of these methods is includedas part of each test method's description in 1207.2.See the Introduction to 1207.2for specific leak test method categorization, andsee Limit of Detection for additional information regardingdeterministic and probabilistic test methods.

关于这些方法的概率性质的更多信息包含在1207.2中，作为每种测试方法说明的一部分。有关特定的泄漏测试方法分类，请参见<1207.2>中的介绍，有关确定性和概率测试方法的其他信息，请参见“探测限”。

Physicochemical versus Microbiological Methods

物理化学方法 vs微生物学方法

“Physicochemical leak testmethods” are those that use physical and/or chemical analysis techniques totest for package integrity. Physicochemical methods include both deterministicand probabilistic leak test methods. “Microbiological leak test methods” areprobabilistic methods of analysis that use viable microorganisms or microbialspores to evaluate test sample integrity. This includes the microbial challengetest by immersion exposure.

“物理化学泄漏测试方法”是使用物理和/或化学分析技术来测试包装完整性的方法。物理化学方法包括确定性和概率泄漏测试方法。“微生物泄漏测试方法”是使用活微生物或微生物孢子评估测试样品完整性的概率分析方法。这包括通过浸没暴露进行的微生物攻击测试。

For definitive package integrity analysis, the use of validated andappropriately sensitive leak test methods is fundamental. Historically,microbiological tests have been used to demonstrate the container–closureintegrity of sterile product presentations. More appropriately, microbiologicaltests may be used when: 1) no adequate physicochemical leak test method exists,2) the product package proves incompatible with known physicochemical leak testmethods, or 3) the desired test method outcome depends on a microorganismchallenge. For example, the closure system of a multiple-dose, nonpreservedproduct may include sterilizing filters or other mechanisms for ensuringsterile product delivery. The validation of unpreserved multiple-dosecontainers must ensure that the package allows safe delivery of the productwithout microbial ingress. The following section includes additional informationon the test method outcome criterion that is related to the microbiologicalchallenge test method.

对于确定的包装完整性分析，使用经过验证且适当敏感的泄漏测试方法至关重要。从历史上看，微生物测试已被用来证明无菌产品的容器密闭性。更适当地，在以下情况下可以使用微生物学测试：1）不存在适当的物理化学泄漏测试方法，2）产品包装证明与已知的物理化学泄漏测试方法不兼容，或3）所需测试方法的结果取决于微生物的挑战。例如，多剂量，非防腐产品的封闭系统可包括灭菌过滤器或其他机制，以确保无菌产品的输送。未经保存的多剂量容器的验证必须确保包装能够安全地运送产品而不会被微生物侵入。以下部分包括与微生物挑战测试方法有关的测试方法结果标准的其他信息。

Method Outcome and Quantitative versusQualitative Measures of Analysis

方法结果和定量分析方法vs定性分析方法

The choice of leak test method depends on the specific outcome(s) thatare sought. These outcomes may include: 1) detecting the presence of leak path(s),2) determining the location of leak path(s), 3) measuring leak rate for thewhole package, and 4) evaluating the potential for microbial ingress.

泄漏测试方法的选择取决于所寻求的特定结果。这些结果可能包括：1）检测泄漏路径的存在，2）确定泄漏路径的位置，3）测量整个包装的泄漏率，以及4）评估微生物入侵的可能性。

By definition, all leak test methods are meant to identify the presenceof leak path(s). Often, leak tests are able to provide additional outcomeinformation. Methods that also provide evidence of leak path location includeelectrical conductivity and capacitance tests, bubble emission tests, tracergas sniffer probe tests, and some tracer liquid tests. Methods that provide ameasure of whole-package leak rate include laser-based headspace analysis, massextraction, pressure and vacuum decay methods, and tracer gas tests by the vacuummode. Microbial challenge tests provide an understanding of the degree ofprotection afforded by the product packaging against microbial ingress thatoccurs via active growth or motility through leak pathways and/or by passivetransport via liquids that pass through leak pathways. In summary, all leaktest methods at minimum detect leaks; some methods may provide moreinformation, but no method can yield all four outcomes listed above. Whenselecting a leak test method, one should also consider the measure of analysis,i.e., does the method yield quantitative data that allow for objectiveanalysis, or data that are strictly qualitative and require more subjectiveinterpretation? Leak test methods that use a “quantitative measure of analysis”include electrical conductivity and capacitance tests, laser-based gas headspaceanalysis, mass extraction, pressure and vacuum decay, tracer gas tests (especiallywhen testing via the vacuum mode), and tracer liquid tests that usequantitative analysis (e.g., spectrophotometric analysis).

根据定义，所有泄漏测试方法均旨在识别泄漏路径的存在。通常，泄漏测试能够提供其他结果信息。还提供泄漏路径定位证据的方法包括电导率和电容测试、气泡发射测试、示踪气体嗅探探针测试以及一些示踪液体测试。可以测量整个包装泄漏率的方法包括基于激光的顶空分析、质量提取、压力和真空衰减方法，以及通过真空模式进行的示踪气体测试。微生物攻击测试可帮助您了解产品包装所提供的防护等级，以防止由于微生物通过泄漏通道的主动生长或运动和/或通过泄漏通道的液体的被动运输而发生的微生物入侵。总而言之，所有泄漏测试方法都应至少检测泄漏。有些方法可能会提供更多信息，但没有一种方法可以产生上面列出的所有四个结果。在选择泄漏测试方法时，还应该考虑分析方法，即该方法是否产生了可以进行客观分析的定量数据，还是严格定性且需要更多主观解释的数据？使用“定量分析”的泄漏测试方法包括电导率和电容测试，基于激光的气体顶空分析、质量提取、压力和真空衰减、示踪气体测试（尤其是在通过真空模式进行测试时）和示踪液体使用定量分析（例如，分光光度分析）的测试。

Conversely, a “qualitative measure of analysis” is based on subjectiveobservation of a specific quality, attribute, or characteristic of the testsample, e.g., a visual check for turbidity when evaluating microbial challengetest samples. Bubble emission tests report visible evidence of continuousbubbling, and tracer liquid tests rely on visible evidence of dye migration. Becausequalitative measurement results are subject to interpretation, they may beprone to human error. When the desired method outcome and other methodconsiderations permit, leak test methods that yield quantitative measurementsshould be used.

相反，“分析的定性方法”是基于对测试样品的特定质量，属性或特性的主观观察，例如在评估微生物激发测试样品时对浊度的目视检查。气泡排放测试报告可见连续鼓泡的迹象，示踪剂液体测试依赖于染料迁移的可见证据。由于定性测量结果易于解释，因此可能容易出现人为错误。当所需的方法结果和其他方法考虑因素允许时，应使用能够进行定量测量的泄漏测试方法。

Limit of Detection

探测限

The “limit of detection” of aleak test is the smallest leakage rate or leak size that the method canreliably detect, given the product–package of interest. The PackageIntegrity Test Method Leak Detection Index (below) may be used for expressingthe smallest leaks detectable by any leak test method, and its followingsection, Establishing the Limit of Detection,illustrates how to use this index to express the limit of detection for anyleaktest method.

泄漏测试的“探测极限”是给定关注的产品-包装，该方法可以可靠地检测到的最小泄漏率或泄漏量。封装完整性测试方法泄漏检测指标（如下）可用于表示通过任何泄漏测试方法可检测到的最小泄漏，其下一节“建立探测极限”说明如何使用此指标来表示任何泄漏测试方法。

PACKAGE INTEGRITY TEST METHOD LEAK DETECTIONINDEX

包装完整性测试方法检漏指标

The Package Integrity Test Method Leak Detection Index (Table 1) is a guide to the leak detection capabilities of package integritytest methods. Manufacturers of leak test instruments and authors ofpeer-reviewed leak test studies have reported the test method limit ofdetection in various ways, including smallest hole size detected, smallest gasleak rate detected, and smallest volume of leaking liquid detected. The indexis intended to overcome the confusion that can result from a multiplicity ofunits of measure. To this end, the index defines package leak sizes detectableaccording to a numeric scale that corresponds to orifice size, assuming aperfect hole of negligible length, as well as to the rate at which dry air leakwould pass through such a hole when exposed to 1 atmosphere (atm) differentialpressure at a specified temperature.

包装完整性测试方法泄漏检测指标（表1）是包装完整性测试方法泄漏检测功能的指南。泄漏测试仪器的制造商和同行评审的泄漏测试研究的作者以各种方式报告了检测方法的探测极限，包括检测到的最小孔径、最小的气体泄漏率和最小的泄漏液量。该指标旨在克服因多种计量单位引起的混乱。为此，该指标定义了可根据与孔口尺寸相对应的数字刻度来检测的包装泄漏尺寸，假设孔的长度可以忽略不计，以及暴露在暴露于空气中的干燥空气泄漏通过该孔的速率。在指定温度下为1个大气压（atm）压差。

This index is referenced in <1207.2>to express the smallest to largest leak sizes detectable by each genericintegrity test method. The index also may be used to describe the limit ofdetection of a specific, validated package integrity test method, asillustrated in the following section.

<1207.2>中引用了该索引，以表示每种通用完整性测试方法可检测到的最小到最大泄漏量。该索引还可以用于描述特定的，经过确认的包装完整性测试方法的探测极限，如下节所示。

Ranking test methods as better or worse strictly according to theirlimit of detection index classification should be avoided. A method with alimit of detection index classification of 1 is not necessarily superior to onewith a limit of detection index classification of 3. Often, the best method fora given application is dictated by other factors. For example, a tracer gasleak test method (limit of detection index classification 1) may be the properchoice for establishing the optimal capping parameters of a stoppered glassvial during package development but would be an inappropriate choice fortesting the same package filled with product in routine manufacturing. Instead,an electrical conductivity and capacitance test (limit of detection indexclassification 3) may be the best option.

应避免严格按照检测指标分类的限度对测试方法的优劣进行分级。检测指标分类极限为1的方法不一定优于检测指标分类极限为3的方法。通常，给定应用程序的最佳方法由其他因素决定。例如，示踪气体泄漏测试方法（检测指标分类为1的极限）可能是在包装开发过程中建立瓶塞玻璃小瓶的最佳封盖参数的正确选择，但对于测试填充有产品的同一包装可能是不合适的选择在常规制造中。相反，电导率和电容测试（检测指标等级3的极限）可能是最佳选择。

Table 1. Package IntegrityTest Method Leak Detection Index

表1 包装完整性测试方法检漏指标

Limit of Detection Index Classification 探测限指标分类	Detectable Leaks Expressed in Two Different Units of Measure 以两种不同的计量单位表示的可检测泄漏
Limit of Detection Index Classification 探测限指标分类	Air Leakage Rate^a(stdcm³/s) 漏气率	Orifice Leak Size^b(μm) 孔口泄漏尺寸
1	<10 ^-6	<0.1
2	10 ^-6 to 10 ^-4	0.1 to 1
3	6 × 10 ^-4 to 4 × 10 ^-3	2 to 5
4	5.0 × 10 ^-3to 1.6 × 10 ^-2	6 to 10
5	0.017 to 0.360	11 to 50
6	> 0.36	>50

^a Dry air leak rate measured at 1 atmdifferential pressure across an orifice leak (i.e., leakinlet pressure of 1 atm versus outlet pressure of approximately 1 Torr)at 25°. The theoreticalcorrelations of orifice sizes to air leakage rates were provided by Lenox Laser,Glen Arm, MD. Leakage rates are approximation ranges.

干燥空气泄漏率是在25°时在孔口泄漏处以1个大气压的差压测量的（即，泄漏入口压力为1个大气压，出口压力约为1托）。孔口尺寸与漏气率的理论关系由马里兰州Glen Arm的Lenox Laser提供。泄漏率是一个近似范围。

b Nominal diameterorifice sizes assume a leak path of negligible length. Orifice sizes areapproximation ranges.

公称直径孔的尺寸假设泄漏路径的长度可以忽略不计。孔口尺寸是近似范围。

ESTABLISHING THE LIMIT OF DETECTION

建立探测极限

Table 2presentspossible leak test scenarios with associated theoreticaldata. The table provides instruction ononeapproach to establishing the limits of detection for two deterministic and twoprobabilistic methods. This approach uses random-order negative and positivecontrol data generated during a 3-day method validationprogram. The test method acceptance criteria requireall negative controls to pass, and all positive controls with leaks at andabove the claimed limit of detection to fail. In this example, the limit ofdetection for a given method is defined as the smallest-leak positive-controlsubset that consistently demonstrates leakage in 100% of the positive-controlsubset units at that defect size and larger. (The percentage of positivecontrols that must be detected to define the limit of detection should bespecified in the validation study protocol by the end-user.)

表2列出了可能的泄漏测试方案以及相关的理论数据。下表提供了两种确定性方法和两种概率性方法建立探测限的一种方法的说明。这种方法使用在3天的方法验证程序中生成的随机顺序的阴性和阳性对照数据。测试方法的接受标准要求所有阴性对照都必须通过，而所有泄漏达到或超过要求的探测极限的阳性对照都必须通过。在此示例中，将给定方法的探测极限定义为最小泄漏的阳性对照子集，该子集始终证明在该缺陷大小及更大的情况下100％的阳性对照子集单元发生泄漏。（最终用户应在验证研究方案中指定必须检测以定义探测限的阳性对照的百分比。）

Table 2. Instructional Example Scenarios for Determination of Leak TestMethod Limit of Detection

确定泄漏测试方法的探测限的指导性示例场景

POSITIVE CONTROLS DETECTED AS LEAKING USING THE SPECIFIED TEST METHOD (%) 使用指定的测试方法检测到的阳性对照（％）
Positive Control Leak Sizes (μm) 阳性对照泄漏尺寸	DETERMINISTIC LEAK TEST METHODS 确定性泄漏测试方法						PROBABILISTIC LEAK TEST METHODS 概率性泄漏测试方法
		A			B			C			D
	Day 1	Day 2	Day 3	Day 1	Day 2	Day 3	Day 1	Day 2	Day 3	Day 1	Day 2	Day 3
2	90	85	93	0	0	0	30	0	0	0	0	2
5	100	100	100	0	0	0	100	3	20	0	3	3
10	100	100	100	20	10	0	100	0	60	50	20	20
15	100	100	100	91	100	83	100	60	100	40	100	35
25	100	100	100	100	100	100	100	100	100	80	50	100
50	100	100	100	100	100	100	100	100	100	100	100	100
Leak Test method: LOD^a 泄漏测试方法：	5μm	5μm	5μm	25μm	15μm	25μm	5μm	25μm	15μm	50μm	50μm	25μm
Day of test LOD: Leak size classification 测试日期LOD：泄漏尺寸分类	3	3	3	5	5	5	3	5	5	6	6	5
Day of test LOD: Leak size classification 测试日期LOD：泄漏尺寸分类	3			5			Variable-LOD to be defined each test day 每个测试日都要定义可变LOD			Variable-LOD to be defined each test day 每个测试日都要定义可变LOD

^a LOD, limit of detection. LOD-探测限

[NOTE—This table represents possibleleak test scenarios with associated theoretical data to provide instruction onone approach to establishing the limits of detection for two deterministic andtwo probabilistic leak test methods.]

[注：该表代表了可能的泄漏测试场景以及相关的理论数据，为建立两种确定性和两种概率泄漏测试方法的检出限的一种方法提供了指导。]

The tabulated data are further discussed below by test method:下表通过测试方法进一步讨论数据：

Deterministic test method A. All positive controls 5 µm and larger were detected on all three testdays.All negative controls passed. Therefore, the final limit of detectionfor this method is 5 µm, and the corresponding limit of detection leak size classificationfor this method is class 3.

确定性测试方法A。在所有三个测试日中检测到所有5 µm及更大的阳性对照。所有阴性对照均通过。因此，此方法的最终探测极限为5 µm，此方法的相应检测泄漏尺寸分类的极限为3级。

Deterministic test method B. All positive controls 25 µm and larger (class 5) were detected on test Days1 and 3. On Day 2, the test found all defects15 µm and larger (class 5). The final limit of detection forthismethod is 25 µm (class 5).

确定性测试方法B。在测试的第1天和第3天检测到所有25 µm和更大（5级）的阳性对照。在第2天，测试发现所有15 µm和更大（5级）的缺陷。此方法的最终探测极限为25 µm（5级）。

Probabilistic test method C. The leak size subsets in which all positive controls were detected variedfrom5 µm (class 3) to 25 µm (class 5) to 15 µm (class 5) on Days 1, 2,and 3,respectively. Because of the day-to-day variation in results, a final limit ofdetection cannot be established. Therefore, the limit of detection is to beassessed each time the test is to be performed.

概率性测试方法C。在第1天，第2天和第3天检测到所有阳性对照的泄漏量子集分别从5 µm（3级）到25 µm（5级）到15 µm（5级）变化。由于结果的每日变化，无法确定最终的探测限。因此，每次执行测试时都要评估探测限。

Probabilistic test method D. The leak size subsets in which all positive controls were detected were50µm (class 6) on Day 1 and 25 µm (class 5) on Day 3.On Day2, the method showed 100% leak detection for 15-µmdefects, but not all of the 25µm defects were detected. The Day 2limit of detection is 50 µm (class 6), as detection of smaller defects cannotbe guaranteed. Because of the variability in test results, a final limit of detectioncannot be established. Therefore, the limit of detection is to be assessed eachtime the test is to be performed.

概率性测试方法D。在第1天检测到所有阳性对照的泄漏尺寸子集分别为50 µm（第6类）和在第3天检测为25 µm（第5类）。在第2天，该方法显示了对15µm的100％泄漏检测。缺陷，但并非所有25µm缺陷都被检测到。第2天的探测极限为50 µm（6级），因为不能保证检测到较小的缺陷。由于测试结果的差异，无法确定最终的探测限。因此，每次执行测试时都要评估探测限。

In summary, the limit ofdetection—the smallest-leak positive-control subset that consistentlydemonstrated leakage in 100% of the subset units of a given defect size andlarger—was clearly demonstrated for the two deterministic test methods, Aand B.Therefore, routine testing by either method for this particular product–package application would require no further verification of leak detectioncapability.

总而言之，对于两种确定性测试方法A和B，清楚地证明了探测限-最小泄漏的阳性对照子集，该子集始终证明在给定缺陷大小和较大缺陷的子集单元中100％发生泄漏。对于这种特殊的产品-包装应用，通过任何一种方法进行的常规测试都无需进一步验证泄漏检测功能。

Neither of the theoretical datasets from probabilistic test methods Cand Ddemonstrated consistency. Therefore, positive and negative controls would berecommended for inclusion with the test sample population during routine testingto verify the day-of-test limit of detection. As more data are generated, alimit of detection might be established for method C and/or methodD, eliminating the need for routine inclusion of positive and negativecontrols.

概率测试方法C和D的理论数据集均未显示出一致性。因此，在常规测试期间，建议将阳性和阴性对照纳入测试样品群，以验证检测日的探测限。随着生成更多数据，可能会为方法C和/或方法D建立探测极限，从而无需常规包含阳性和阴性对照。

Largest Leak Detection Capability

最大的泄漏检测能力

When selecting a leak test method, one should consider the method'sability to detect the smallest leaks as well as the largest defects that arepotentially present. A method's largest leak detection capability is theability of the method to detect larger leaks of a given size or defect type(i.e., the upper limit of the leak detection range). It is incorrect to assumethat a leak test method capable of detecting the smallest leaks can also findlarger leaks. As with all analytical methods, each leak test has an optimummeasurement range. For example, tracer gas leak test methods are the mostsensitive methods, able to detect leaks as small as E-10 stdcm³/s.Yet this approach may miss leaks many-fold larger that allow rapid escape ofthe tracer gas before the test sample can even be tested. Similarly, massextraction and vacuum decay leak test methods may miss larger leaks if test packageheadspace gas is removed during the pre-test sample chamber evacuation phase,leaving little gas to leak out of the package during the final test phase. Froma practical standpoint, mass extraction or vacuum decay may be able to detect atiny, laser-drilled hole in a 2-mL vial package with minimal headspace, butthese same tests could conceivably fail to identify a missing stopper.

选择泄漏测试方法时，应考虑该方法检测最小泄漏和最大潜在缺陷的能力。方法的最大泄漏检测能力是该方法检测给定大小或缺陷类型（即，泄漏检测范围的上限）的较大泄漏的能力。认为能够检测到最小泄漏的泄漏测试方法也会发现较大泄漏是不正确的。与所有分析方法一样，每个泄漏测试都具有最佳的测量范围。例如，示踪气体泄漏测试方法是最灵敏的方法，能够检测到E-10 stdcm³ / s的泄漏。然而，这种方法可能会漏掉比常规方法大很多倍的泄漏，这使得示踪剂气体在测试样品被检测之前就能快速逸出。同样，如果在预测试样品室抽空阶段除去测试包装的顶空气体，则质量提取和真空衰减泄漏测试方法可能会漏掉较大的泄漏，而在最后的测试阶段，几乎没有气体泄漏出包装。从实际的角度来看，质量提取或真空衰减可能能够在2 mL样品瓶包装中以最小的顶空检测出一个很小的激光钻孔，但是可以想象，这些相同的测试可能无法识别出缺少的塞子。

Large leak detection may be important in routine manufacturing wherepackages damaged by catastrophic breakage or are defective due to misassemblycould enter into commercial or clinical study distribution and cause patientharm. In addition, some instruments may malfunction or become damaged uponexposure to large leaks. Thus, leak test method selection should always takeinto account the largest leak sizes likely to occur in the test sample population.

在常规生产中，大泄漏检测可能很重要，在常规生产中，由于灾难性损坏而损坏的包装或由于组装错误而造成的包装缺陷可能会进入商业或临床研究范围并造成患者伤害。此外，某些仪器在暴露于大泄漏时可能会发生故障或损坏。因此，泄漏测试方法的选择应始终考虑到测试样品总体中可能发生的最大泄漏量。

To demonstrate a leak test method's largest leak detection capability,large-leak positive controls should represent defects anticipated for the givenproduct–package. These defects may be defined by size, such as the diameter ofa hole drilled through a pouch package (intended to simulate a needle-puncturedefect). Alternatively, positive-control packages exemplifying actual packagefailure modes may be used without reference to defect size. Examples include avial with a missing stopper, a syringe with a needle piercing the needleshield, or a pouch with a gap in the seal.

为了证明泄漏测试方法最大的泄漏检测能力，大泄漏阳性对照应代表给定产品-包装所预期的缺陷。这些缺陷可以通过尺寸来定义，例如通过袋包装所钻的孔的直径（旨在模拟针刺缺陷）。可替代地，可以使用例示实际包装件故障模式的正控制包装件，而无需参考缺陷尺寸。示例包括带有缺少的塞子的小瓶，带刺穿针头护罩的针头的注射器或在密封件中有缝隙的小袋。

When identifying the largest leak sizes that a given method can detect,one may refer to the Package Integrity Test Method Leak DetectionIndex (Table 1). The generic methods described in <1207.2>discuss the leak size detection range for each testing approach according tothis scale.

当确定一种给定方法可以检测到的最大泄漏量时，可以参考包装完整性测试方法泄漏检测指标（表1）。在 <1207.2>中描述的通用方法根据该等级讨论每种测试方法的泄漏尺寸检测范围。

Nondestructive versus Destructive Methods

非破坏性方法vs 破坏性方法

The need to preserve the product–package may influence the decision toselect a nondestructive leak test method, rather than a destructive one. Destructivetest methods damage the test sample and/or expose it to potential contaminants;hence, the product is not recoverable. Only nondestructive test methods areappropriate for leak testing a product intended for commercial or clinicalstudy distribution. Examples of destructive leak test methods include tracerliquid ingress tests, bubble emission tests, and microbiological challengetests.

保存产品包装的需求可能会影响选择非破坏性泄漏测试方法而非破坏性测试方法的决定。破坏性的测试方法会损坏测试样品和/或使其暴露于潜在的污染物；因此，该产品不可回收。仅非破坏性测试方法适用于对打算用于商业或临床研究分销的产品进行泄漏测试。破坏性泄漏测试方法的示例包括示踪剂液体侵入测试，气泡排放测试和微生物挑战测试。

Examples of nondestructive leak test methods include mass extraction andvacuum decay leak tests, as well as noninvasive gas headspace analysis tests.Electrical conductivity and capacitance leak tests are deemed nondestructiveonce the impact of electrical current on the product's physicochemical stabilityhas been verified through stability-indicating assays; in rare instances,exposure triggers headspace ozone formation, causing product oxidation (5).

无损泄漏测试方法的示例包括质量提取和真空衰减泄漏测试以及无创气体顶空分析测试。一旦通过稳定性指示测定法验证了电流对产品的物理化学稳定性的影响，则认为电导率和电容泄漏测试无损。在极少数情况下，暴露会触发顶空臭氧的形成，导致产品氧化（5）。

Off-Line versus On-Line Methods

离线与在线方法

Off-line leak test methods are generally performed on a stratifiedrandom sampling of the product, thus limiting the ability of the test to identifypotential integrity problems. Off-line leak tests may be nondestructive ordestructive. Destructive leak tests can be used only off-line and includemethods such as pressure decay, bubble emission tests, tracer-liquid tests, andmicrobiological challenge tests. Tracer gas tests are considered destructive ifthey require tracer-gas introduction into the package after package assembly.Off-line testing may also include seal quality checks.

离线泄漏测试方法通常在产品的分层随机抽样上执行，因此限制了测试识别潜在完整性问题的能力。离线泄漏测试可能是非破坏性的或破坏性的。破坏性泄漏测试只能离线使用，包括压力衰减，气泡排放测试，示踪剂测试和微生物挑战测试等方法。如果在包装组装后要求将示踪气体引入包装中，则示踪气体测试被认为具有破坏性。离线测试也可能包括密封质量检查。

An on-line leak test method for entire lot testing must benondestructive to the package and its contents and must be rapid enough to allowfor incorporation into manufacturing operations. On-line testing providesgreater assurance that all packages are integral and yields instant feedback inthe event of package misassembly or breakage, enabling real-time linecorrections. Examples of leak test methods commonly performed on-line includeelectrical conductivity and capacitance, vacuum decay leak, and noninvasivelaser-based gas headspace analysis tests. If the production line cannotaccommodate the integrity test method due to factors such as instrument footprintor testing speed limitations, then product leak testing may be performedoff-line.

用于整批测试的在线泄漏测试方法必须对包装及其内容无损，并且必须足够快以允许纳入制造过程。在线测试可更好地确保所有包装都是完整的，并在包装错误组装或破损时提供即时反馈，从而可以进行实时生产线校正。通常在线执行的泄漏测试方法的示例包括电导率和电容，真空衰减泄漏和基于激光的非侵入性气体顶空分析测试。如果生产线由于仪器占地面积或测试速度限制等因素而无法采用完整性测试方法，则可以离线进行产品泄漏测试。

TEST INSTRUMENT QUALIFICATION, METHODDEVELOPMENT, AND METHOD VALIDATION

测试仪器鉴定、方法开发和方法确认

Physicochemical leak test methods are proven effective by performinganalytical test instrument qualification, followed by test method developmentand validation. The following three method validation strategies are no longerconsidered best practice.

通过进行分析测试仪器的鉴定，然后进行测试方法的开发和验证，可以证明物理化学泄漏测试方法是有效的。以下三种方法验证策略不再被视为最佳实践。

RELIANCE ON MICROBIAL INGRESS COMPARISONS

依赖微生物侵入比较

Physicochemical leak test method validation formerly included a director indirect comparison of physicochemical leak test results to microbiologicalimmersion challenge data generated for the product– package. This approach isnot supported, because the peer-reviewed literature shows consistently that commonlyavailable physicochemical leak tests are inherently more sensitive,deterministic, and robust than are microbiological methods. Because microbialingress is such a probabilistic event, the use of microbial ingress methodsrequires thorough and well-designed test protocols. These protocols need to uselarge population sets of negative and positive controls to generate meaningfulmicrobial ingress risk assessments. In addition, because test performancedeclines sharply with reduced leak size, it is difficult to design, develop,validate, and implement microbial ingress methods that are reliable andpredictable.

物理化学泄漏测试方法的确认，以前包括直接或间接比较物理化学泄漏测试结果与产品包装产生的微生物浸没挑战数据。不支持这种方法，因为经过同行评审的文献一致地表明，与微生物方法相比，通常可用的物理化学泄漏测试在本质上更灵敏、确定性更强。由于微生物入侵是一种概率事件，因此使用微生物入侵方法需要彻底且设计良好的测试协议。这些协议需要使用大量的阴性和阳性对照来产生有意义的微生物入侵风险评估。此外，由于测试性能随着泄漏尺寸的减小而急剧下降，因此难以设计、开发、确认和实施可靠且可预测的微生物入侵方法。

MISAPPLICATION OF STANDARD METHODS

标准方法的误用

It is incorrect to assume that a recognized standard method (e.g., ASTMor ISO) is ready to use for evaluating any and all product–package systems.Typically, such methods are written in a generic manner, and they requirefurther optimization and validation geared towards specific product–packageapplications. It is also incorrect to assume that the elastomeric closure functionalityself-sealing capacity test (a dye ingress method)in USP ElastomericClosures for Injections <381> is a validatedpackage integrity test method. This test is intended solely for detecting grossfailure of elastomeric closures intended for multiple-dosage package systems.

假定公认的标准方法（例如ASTM或ISO）可用于评估任何及所有产品包装系统是不正确的。通常，此类方法是以通用方式编写的，它们需要针对特定产品-包装应用程序进行进一步的优化和验证。假设USP注射用弹性体密封件<381>中的弹性体密封件功能性自密封能力测试（染料进入方法）是经过验证的包装完整性测试方法也是不正确的。该测试仅用于检测用于多剂量包装系统的弹性密封件的严重故障。

RELIANCE SOLELY ON INSTRUMENT LIMIT OF DETECTION

仅依靠仪器的探测极限

Instrument limit of detection data do not suffice for test method limit ofdetection verification. For example, thelimit of detection for the dye ingress test method has been equated tothe lowest concentration of dye detectable in a standard solution. However,this approach presumes that this minimal amount of detectable dye will alwaysenter defective packages under given test conditions, an assumption refuted bysubsequent research (6). Similarly, vacuum decay and mass extraction leak test systems havebeen checked for limit of detection by introducing a leak of unrestricted,unlimited air supply into the test system via a calibrated airflow meter orstandard orifice. This approach verifies instrument functionality but fails toprove that these methods are capable of detecting actual, randomly occurringleaks in product–packages. The performance of such methods is affected bypackage headspace volume, package component outgassing, and product blockage ofleak path (7, 8).

仪器的检测数据极限不能满足检测方法的检测验证极限。例如，染料进入测试方法的检出限等于标准溶液中可检测到的最低染料浓度。但是，这种方法假定在给定的测试条件下，这种最小量的可检测染料将始终进入有缺陷的包装中，这一假设遭到后续研究的反驳（6）。同样，已经通过校准空气流量计或标准孔将无限制，无限制的空气供应泄漏引入测试系统，从而检查了真空衰减和质量提取泄漏测试系统的探测极限。该方法验证了仪器的功能，但未能证明这些方法能够检测产品包装中实际，随机发生的泄漏。此类方法的性能受包装顶空体积，包装组件脱气和产品泄漏路径阻塞的影响（7、8）。

Instrumentation and Equipment Qualification

仪器设备资质

The qualification of instruments or equipment to be used for leaktesting includes: 1) evaluation of instrument/equipment functionality, and 2)determination of test system limit of detection using appropriate calibrationtools or reference standards to simulate with-leak test conditions. Forexample, microbial challenge testing by immersion exposure uses vessels thatcan maintain predetermined vacuum conditions for the exposure duration requiredand also uses incubators able to maintain temperature and humidity conditionswithin specified ranges. A general overview of analytical instrumentqualification is presented in Analytical Instrument Qualification <1058>.Chapter <1207.2> providesqualification guidance unique to each leak test method, including limit ofdetection standards.

用于泄漏测试的仪器或设备的资格包括：1）评估仪器/设备的功能，以及2）使用适当的校准工具或参考标准来模拟泄漏测试条件，确定测试系统的探测极限。例如，通过浸没暴露进行的微生物攻击测试使用的容器可以在所需的暴露时间内保持预定的真空条件，还使用能够将温度和湿度条件保持在指定范围内的培养箱。分析仪器认证<1058>中介绍了分析仪器认证的一般概述。 <1207.2>章提供了每种泄漏测试方法所独有的资格认证指南，包括检测标准限值。

Method Development

方法开发

After successful qualification, leak test method parameters aredeveloped and optimized to ensure sensitive, accurate, robust, and reproducibleleak detection for specific product–package systems. Negative and positivecontrols are designed and assembled appropriately with consideration ofcontainer–closure design, materials of construction, characteristics ofanticipated package leaks, and impact of product contents on test results. Therobustness of a leak test method relates to the method's ability to accuratelyidentify leaking versus nonleaking packages, given test conditions bracketingoptimal or normal test specifications. For example, the robustness of a vacuumdecay leak test with a test cycle time of 30 s might be demonstrated duringmethod development byverifying methodperformance at test cycle times of 28 and 32 s. Chapter <1207.2 > elaborates on leak test methoddevelopment considerations that are relevant to various product–package systems.

成功通过鉴定后，将开发和优化泄漏测试方法参数，以确保针对特定产品-包装系统的灵敏，准确，可靠且可重现的泄漏检测。阴性和阳性对照的设计和组装要考虑到容器密闭设计，结构材料，预期的包装泄漏特征以及产品内容对测试结果的影响。在给定最佳或正常测试规格的测试条件下，泄漏测试方法的鲁棒性与该方法准确识别泄漏和非泄漏包装的能力有关。例如，可以通过在28和32 s的测试周期内验证方法性能来证明在方法开发过程中具有30 s的测试周期时间的真空衰减泄漏测试的鲁棒性。 <1207.2>详细介绍了与各种产品包装系统相关的泄漏测试方法的开发注意事项。

Method Validation

方法确认

General concepts of analytical methods validation are discussed indetail in Validation of CompendialProcedures <1225>. Methodaccuracy is the ability of a leak test to correctly identify or size leaks (asper the intended leak test outcome). Method precision is a measure of testresult reproducibility and is proven during method validation by testing arandomly mixed population of negative and positive controls over multiple daysby multiple operators and, when possible, using multiple test instruments.Acceptance criteria for leak test method validation should include thefollowing: 1) all negative controls pass (no leaks are identified), and 2) allpositive controls with leaks at or above the designated limit of detection fail(leaks are detected). For some test methods, test blanks are also included aspart of method validation and routine testing. For example, liquid tracer leakdetection by spectrophotometric analysis may require a comparison of testresults to results of a blank solution without the liquid tracer element.Blanks are not equivalent to, and should not substitute for, negative controls.

分析方法确认的一般概念在药典程序的确认<1225>中详细讨论。方法准确性是泄漏测试正确识别泄漏或确定泄漏大小的能力（根据预期的泄漏测试结果）。方法精度是测试结果可重复性的一种度量，并且在方法确认期间通过由多个操作员在可能的情况下使用多个测试仪器测试随机混合的阴性和阳性对照群体的随机数来证明。泄漏测试方法确认的接受标准应包括以下内容：1）所有阴性对照均合格（未发现泄漏），以及2）所有阳性泄漏量等于或高于指定探测极限的阳性对照（检测到泄漏）。对于某些测试方法，测试空白还包括在方法确认和常规测试中。例如，通过分光光度分析进行液体示踪剂泄漏检测可能需要将测试结果与没有液体示踪剂元素的空白溶液的结果进行比较。空白不等同于阴性对照，也不能替代阴性对照。

Positive and Negative Controls

阳性对照和阴性对照

“Positive controls” are packageswith no known leak, and negative controls are packages with intentional orknown leaks. Positive and negative controls represent packages that wereassembled in a typical manner using normally processed components, with theexception of the intentionally created leak in the positive control subset. Whendesigning control packages, one should consider the potential impact ofproduct, packagecomponents, and package assembly variables on the test method'sperformance; this is because test results influenced inadvertently by suchvariables may complicate data interpretation.

“阳性对照”是没有已知泄漏的包装，阴性对照是有意或已知泄漏的包装。阳性对照和阴性对照表示使用正常处理的组件以典型方式组装的包装，除了阳性对照子集中有意产生的泄漏外。设计控制包装时，应考虑产品，包装组件和包装装配变量对测试方法性能的潜在影响；这是因为测试结果受此类变量的无意影响可能会使数据解释复杂化。

Defect Creation Methods

缺陷创建方法

Ideally, the positive control set represents a range of package defectsizes and types. Numerous approaches have been used to create package defects.Leakage dynamics are clearly different for different defect types and materialsof construction, and this should be considered when creating positive controls.

理想情况下，阳性对照集代表包装缺陷尺寸和类型的范围。已经使用了许多方法来产生封装缺陷。对于不同的缺陷类型和构造材料，泄漏动力学明显不同，因此在创建阳性对照时应考虑到这一点。

Placing a “hole” or break in the package wall is one approach. Thedefect materials of construction are identical to the package itself, whichallows for investigation into any interference with the leak test method causedby product exposure to the package defect surface. Laser drilling is often usedto create package hole defects; however, such holes are actually not pristineorifices but rather consist of a tortuous matrix of paths and micro-cracks. Amicropipette can also be used to simulate a single-orifice hole defect.Insertion of the micropipette requires adhering the pipette wall to the packageusing an appropriate sealant. The challenges of micropipette use includeestablishing a complete seal of the micropipette perimeter to the package andavoiding micropipette tip damage.

在包装壁上放置“洞”或破裂是一种方法。构造上的缺陷材料与包装本身相同，因此可以调查由于产品暴露于包装缺陷表面而对泄漏测试方法产生的任何干扰。激光打孔通常用于制造封装孔缺陷。但是，这些孔实际上不是原始孔，而是由曲折的路径矩阵和微裂纹组成。微量移液器还可用于模拟单孔孔缺陷。微量移液器的插入需要使用适当的密封剂将移液器壁粘附到包装上。使用微量移液器的挑战包括建立微量移液器周边与包装的完全密封以及避免微量移液器尖端损坏。

Microtubes (also called microcapillaries) of a given diameter and lengthintended to mimic a smaller-bore, shorter-length leak path can be useful whenperforming leak tests that rely on gas flow measurements. However, it isinappropriate to use lengthy, large-bore microtubes to simulate an orifice leakof smaller diameter when performing leak tests that rely on the passage of liquidsor microorganisms. Liquid flow into and through a microtube is affected bynumerous factors including liquid surface tension, liquid viscosity, surfacecontact angle, airlocks, and tube-wall and tube-end finishes. Microbial ingressrelies more on presence of liquid in the tube than on the physical barrier topassage or grow-through afforded by the actual tube diameter (9). Ideally, microtubes should be as long as the actual package barrierthickness (package wall or seal width). Difficulties with microtube use includethose of effecting smooth, perpendicular cuts of microtube ends and ofadequately sealing microtubes into the test sample wall.

当执行依赖于气体流量测量的泄漏测试时，具有给定直径和长度的微管（也称为微毛细管）可以模拟较小口径，较短长度的泄漏路径。但是，在执行依赖于液体或微生物通过的泄漏测试时，使用较长的大口径微管来模拟较小直径的孔泄漏是不合适的。流入和通过微管的液体会受到许多因素的影响，包括液体表面张力，液体粘度，表面接触角，气闸以及管壁和管端涂层。微生物的侵入更多地取决于管中液体的存在，而不是取决于实际管径（9）所提供的通过或生长的物理屏障。理想情况下，微管的长度应与实际包装的阻隔厚度（包装壁或密封宽度）一样长。使用微管的困难包括实现微管端部的光滑垂直切割以及将微管充分密封到测试样品壁中的困难。

Other commonly used defect creation methods include inserting a needlethrough the package wall; placing a wire, microfilament, or film betweensealing surfaces; and adhering a holed, thin metal plate onto package surfaces.A consideration when selecting such approaches is that defects made byinserting a foreign object into the package (e.g., needle, film, wire) canresult in gas, liquid, or microbial leakage dynamics around or through the itemthat may be markedly different from leakage through actual defects (10). In addition, needles left inserted in the package do not representdefects small enough for a meaningful limit of detection leak test challenge.

其他常用的缺陷产生方法包括将针头插入包装壁；在密封表面之间放置金属丝，微丝或薄膜；并将带孔的薄金属板粘附到包装表面。选择此类方法时应考虑的是，通过将异物插入包装（例如，针，薄膜，金属丝）而造成的缺陷可能导致气体，液体或微生物在物品周围或通过物品的泄漏动力学，这些动力学可能与泄漏明显不同。通过实际缺陷（10）。此外，留在包装中的针头并不代表缺陷，不足以对检测泄漏测试提出有意义的限制。

SMALLEST DEFECT SIZES

最小缺陷尺寸

Smallest defects should be as small as reasonably possible, bearing inmind package type, package dimensions, package materials of construction, and defectcreation technology limitations. For example, laser-drilled holes in rigidglass or plastic components are limited to about 2–3 µm in nominal diameter andto about 5– 10 µm in nominal diameter in flexible package materials. (Companiesthat laser-drill holes may certify nominal hole size dimensions using flowmeters, with a laser-drilled orifice in a metal plate as a calibrationstandard). Smaller defects are difficult to create and accurately size and mayeasily close from handling, debris, or flexible package wall deflection.Micropipettes can simulate orifice sizes as small as 0.1 µm in diameter, andmicrotubes could be as small as approximately 2 µm in nominal diameter.

考虑到包装的类型，包装的尺寸，包装的结构材料和缺陷产生技术的局限性，最小的缺陷应尽可能地小。例如，在刚性玻璃或塑料组件中的激光钻孔的公称直径限制为大约2–3 µm，在软包装材料中的公称直径限制为大约5– 10 µm。（激光钻孔的公司可以使用流量计来验证公称孔的尺寸，并将金属板上的激光钻孔作为校准标准）。较小的缺陷很难产生且尺寸难以确定，并且很容易因搬运、碎屑或柔性包装壁偏斜而关闭。微量移液器可以模拟直径小至0.1 µm的孔，微型管的公称直径可能小至约2 µm。

LARGER DEFECT SIZES

最大缺陷尺寸

In addition to smallest size defects, larger size defect-positive controlsshould be included during method development and optimization, because someleak test methods that are able to detect small leaks have a limited ability totest much larger defects. In addition, grossly leaking packages may hamper thereliability and instrument functionality of some leak test methods.

除了最小尺寸的缺陷外，在方法的开发和优化过程中还应包括较大尺寸的缺陷阳性对照，因为某些能够检测到小泄漏的泄漏测试方法测试大缺陷的能力有限。此外，严重泄漏的包装可能会妨碍某些泄漏测试方法的可靠性和仪器功能。

TYPE DEFECTS

缺陷类型

“Type defects” are positivecontrols representing realistic package flaws included in method developmentstudies before method validation. Type defect examples are listed below.

“类型缺陷”是代表方法验证之前方法开发研究中包含的实际包装缺陷的阳性对照。类型缺陷示例如下所示。

l Heat sealed bag: weak seal, wrinkled seal, seal gap, seal channel,product entrapment in seal

热封袋：弱密封，起皱密封，密封间隙，密封通道，产品滞留在密封中

l Stoppered vial package: vial finish channel defect, loosely capped stopper,product trapped between stopper and vial

塞子瓶包装：塞子瓶通道缺陷，塞子盖松动，产品塞在塞子和塞子之间

l Prefilled syringe: needle shield punctured by staked needle, defectiveplunger

预装注射器：针头被刺穿的针头护套，柱塞不良

l Ophthalmic dropper bottle: loose cap, missing or poorly inserted droppertip, defective tip or cap

滴管瓶：盖松动，滴管头缺失或插入不正确，滴头或盖有缺陷

Assigning precise sizes to type defects is generally not meaningful orfeasible because of their inherent irregularity and complexity. For thisreason, type defects are not recommended for use in validation studies thatrequire positive controls with more defined and controlled defect sizes.Rather, type defects are incorporated into leak test method developmentresearch to better understand method capabilities. Because no leak test methodcan find all possible defects in a given container–closure system, informationgleaned from type defect tests can be used to establish controls, therebylimiting the occurrence of critical imperfections not readily found by thechosen leak test method.

由于类型缺陷固有的不规则性和复杂性，为类型缺陷分配精确的尺寸通常没有意义或不可行。因此，不建议将类型缺陷用于确认研究，这些研究需要阳性对照具有更明确和受控的缺陷尺寸。而是将类型缺陷合并到泄漏测试方法开发研究中，以更好地了解方法功能。由于没有泄漏测试方法可以找到给定的容器密闭系统中所有可能的缺陷，因此可以使用从类型缺陷测试中收集的信息来建立控制措施，从而限制了所选泄漏测试方法不易发现的关键缺陷的发生。

MICROBIAL GROW-THROUGH CONTROLS

微生物生长控制

“Microbial grow-through controls”are required for testing the microbial ingress risk that results from microbialgrow-through via growth-supportive product residues left on multiple-dosagepackage closure components or closure product-filtering mechanisms. Positive controlsrequired for these tests must be specifically designed to fit the given product–packagesystem.

测试微生物侵入风险的过程需要“微生物生长控制”，微生物侵入风险是由于多剂量包装封闭组件或封闭产品过滤机制上残留的生长支持性产品残留所致。这些测试所需的阳性对照必须经过专门设计，以适合给定的产品包装系统

REFERENCES参考

1. Department of Health and Human Services. Container and closure systemintegrity testing in lieu of sterility testing as a component of the stabilityprotocol for sterile products. Guidance for industry. Rockville, MD: U.S. Foodand Drug Administration, Center for Biologics Evaluation and Research (CBER),Center for Drug Evaluation and Research (CDER), Center for Devices andRadiological Health (CDRH), Center for Veterinary Medicine (CVM); 2008.

卫生和公共服务部。容器和密封系统的完整性测试代替无菌测试，是无菌产品稳定性规程的组成部分。工业指导。马里兰州罗克维尔（Rockville）：美国食品药品监督管理局，生物评估与研究中心（CBER），药物评估与研究中心（CDER），设备与放射卫生中心（CDRH），兽医医学中心（CVM）； 2008。

2. Bagel S, Wiedemann B. Extension of in-use stability of preservative-freenasalia. Eur J PharmBiopharm. 2004;57(2):353–358.

Bagel S, Wiedemann B扩展无防腐剂鼻液的使用稳定性。 Eur J Pharm Biopharm2004;57(2):353–358.

3. Kirsch LE, Nguyen L, Moeckly CS, Gerth R. Pharmaceuticalcontainer/closure integrity. II: The relationship between microbial ingress andhelium leak rates in rubber-stoppered glass vials. PDA JPharmSci Technol. 1997;51(5):195–202.

4. Kirsch LE, Nguyen L, Moeckly CS, Gerth R. 药品容器/密闭容器的完整性。 II：橡胶塞玻璃瓶中微生物入侵与氦气泄漏率之间的关系。PDA JPharmSci Technol. 1997;51(5):195–202.

5. Kirsch LE. Pharmaceutical container/closure integrity. VI: A report onthe utility of the liquid tracer methods for evaluating the microbial barrierproperties of pharmaceutical packaging. PDA J Pharm SciTechnol. 2000;54(4):305–314.

6. Kirsch LE. Pharmaceutical container/closure integrity. VI: 有关液体示踪法在评估药品包装的微生物屏障性能方面的实用性的报告。PDA J Pharm SciTechnol.2000;54(4):305–314.

7. Bigwarfe P Jr, Domin-Turza A, Hwang E, Leidner S, McGinley C, Olson K,Nachtigall M. Presentation. Annual Meeting of the American Association ofPharmaceutical Scientists 2008. Elucidation of an unusual mechanism of drugproduct degradation caused by a leak detection instrument. Lake Forest, IL:Hospira; 2008.

Bigwarfe P Jr, Domin-Turza A, Hwang E, Leidner S, McGinley C, Olson K,Nachtigall M. Presentation. 2008年美国药学科学家协会年会。阐明由泄漏检测仪器引起的药品降解的异常机制。伊利诺伊州森林湖：霍斯匹拉；2008。

8. Wolf H, Stauffer T, Chen S-C, Lee Y, Forster R, Ludzinski M, Kamat M,Mulhall B, Guazzo D. Vacuum decay container/closure integrity testingtechnology. Part 2. Comparison to dye ingress tests. PDA JPharmSci Technol. 2009;63(5):489–498.

真空衰减容器/盖完整性测试技术。第2部分。与染料进入测试的比较。 PDA J药物科学技术。

9. Yoon S-Y, Sagi H, Goldhammer C, Li L. Mass extraction container closureintegrity physical testing method development for parenteral container closuresystems. PDA J Pharm Sci Technol. 2012;66(5):403–419.

肠胃外容器封闭系统的质量提取容器封闭完整性物理测试方法的开发。

10. Wolf H, Stauffer T, Chen S-C, Lee Y, Forster R, Ludzinski M, Kamat M,Godorov P, Guazzo D. Vacuum decay container/closure integrity testingtechnology. Part 1. ASTM F2338-09 precision and biasstudies. PDA J Pharm Sci Technol. 2009;63:472–488.

真空衰减容器/盖完整性测试技术。第1部分。ASTM F2338-09精度和偏差研究。

9. Keller S, Marcy J, Blakistone B, Hackney C, Carter H, Lacy G.Application of fluid and statistical modeling to establish the leak sizecritical to package sterility. J Appl Pack Res. 2006;1:11–21.

应用流体和统计模型建立对包装无菌至关重要的泄漏量。

10. Morrical BD, Goverde M, Grausse J, Gerwig T, Vorgrimler L, Morgen R,Büttiker J-P. Leak testing in parenteral packaging: establishment of directcorrelation between helium leak rate measurements and microbial ingress for twodifferent leak types. PDA J Pharm Sci Technol.2007;61(4):226–236.2S (USP38)

肠胃外包装的泄漏测试：针对两种不同的泄漏类型，在氦气泄漏率测量值和微生物入侵之间建立直接的相关性。

¹Guidance forindustry: container closure systems for packaging human drugs and biologics,CMC Documentation. Rockville, MD: U.S. Department of Health and Human Services,Food and Drug Administration; 1999.

行业指南：用于包装人类药物和生物制剂的容器密封系统，CMC文档。马里兰州罗克维尔：美国卫生与公共服务部食品和药物管理局； 1999年。

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